Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Astrocytes: biology and pathology

Pathobiology of ischaemic stroke: an integrated view

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.

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IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.

Over the past two decades, research has heavily emphasized basic mechanisms that irreversibly damage brain cells after stroke. Much attention has focused on what makes neurons die easily and what strategies render neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysing drugs has confirmed expectations that early reperfusion improves clinical outcome. With recent research emphasizing ways to reduce tissue damage by both vascular and cell-based mechanisms, the spotlight is now shifting towards the study of how blood vessels and brain cells communicate with each other. This new research focus addresses an important need in stroke research, and provides challenges and opportunities that can be used to therapeutic advantage.

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Mechanisms, challenges and opportunities in stroke

Mechanism of Primary Blast InjuryInsight from Microexplosive Generated Shock Wave-Induced Brain Injury Animal Model and Engineering Experiments: 939

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is undetermined, recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene for MMD among East Asian population. A polymorphism in c.14576G>A in RNF213 was evident in almost all of the familial patients with MMD and 80% of sporadic cases, but the exact role of RNF213 polymorphism in the development of MMD remains unknown. To answer this question, we generated genetically engineered mice lacking Rnf213 by homologous recombination (Rnf213-knockout mice), as well as Rnf213-knock-in mice expressing a missense mutation in mouse Rnf213, p. R4828K, corresponding to human RNF213, p. R4859K, in MMD patients. Although both mice did not spontaneously develop MMD up to 64 weeks of age as shown by high-resolution magnetic resonance angiography and carbon black injection analysis of the circle of Willis, the biological response of these mice under a variety of insults, such as ischemia or immunological stimuli, provided new insights for the pathogenesis of this rare entity.

Pathological Investigation on RNF213: Animal Models of Rnf213-Knockout and Knock-in Mice

https://www.jstage.jst.go.jp/article/jcns/22/9/22_695/_pdf

Issues in moyamoya disease: Consideration for its intrinsic physiologi-cal reorganization system

Various intraventricular tumors can present with calcifications; however, the choroid plexus can also have physiological calcifications. This is the first case report of meningiomas located at the bilateral foramen of Monro (FOM), concealed by a grossly calcified choroid plexus, presenting with obstructive hydrocephalus. A 60-year-old woman with disturbed consciousness was admitted by ambulance. Head computed tomography revealed significantly high-density lesions that smoothly extended from the choroid plexus of the lateral ventricles to the third ventricle. They occupied both sides of the FOM, resulting in obstructive hydrocephalus. The diagnostic endoscopic biopsy was performed using a flexible neuroendoscopic system, and an egg shell-like grossly calcified choroid plexus was found to smoothly extend toward the FOM. Resection was not selected because the calcified lesions had tightly adhered to the veins and fornix; therefore, the patient underwent ventriculo-peritoneal shunting. The lesions were histologically identified as psammomatous meningiomas with low proliferation potential (the Ki-67 labeling index was lower than 1%). She was discharged 10 days after surgery without neurological deficits. As calcifications can have tumoral and nontumoral origins, we considered neuroendoscopic exploration to be essential in order to achieve an accurate diagnosis and select optimal management.

Miki Fujimura

Papers

Mechanism of Primary Blast InjuryInsight from Microexplosive Generated Shock Wave-Induced Brain Injury Animal Model and Engineering Experiments: 939

Pathological Investigation on RNF213: Animal Models of Rnf213-Knockout and Knock-in Mice

Issues in moyamoya disease: Consideration for its intrinsic physiologi-cal reorganization system

Grossly calcified choroid plexus concealing foramen of Monro meningiomas as an unusual cause of obstructive hydrocephalus.

Quantitative assessment of cerebral hemodynamics using single photon emission computed tomography with venous blood sampling